1. Field of the Invention
The present invention generally relates to a method for reducing and preventing cell and tissue damage. More particularly, the present invention is directed to the administration of L-histidine, an amino acid, for the prevention, control, and amelioration of tissue, vessel and cell damage from cytokines and related molecules.
2. Description of the Prior Art
Cytokines are a general class of peptide or glycoprotein molecules which are involved in cell-to-cell signaling and interaction. In particular, these molecules are involved in a variety of immune system and inflammatory responses. The cytokines are numerous and include at least lymphokines, monokines, tumor necrosis factor (TNF), colony stimulating factors (CSFs), growth factors, and interleukins. A number of the cytokines are involved in the stimulation of growth, differentiation and other functions in a variety of target cells. It should be understood that the term cytokine is being used to describe the general group of modulators involved in intercellular interaction and signaling. This term is not intended to be limiting and can include any number of molecules which are involved in these systems, as would be understood by one of ordinary skill in the art.
In contrast to hormones, which are usually continuously produced by discrete glands, cytokines are generally produced after stimulation by virtually every cell type. In addition, a particular cell type can produce a variety of different cytokines.
A number of cytokines have been identified and cloned, however, at present, unique biologic activities can not be determined for most cytokines since nearly all types of cells have multiple receptors for and can respond to a variety of cytokines. In addition, it is thought that there is a considerable overlap in the biologic activities of cytokines. Furthermore, it has been shown that there is a redundancy of action among cytokines.
The characteristics, described supra, enable cellular responses to utilize alternative pathways and allow suboptimal concentrations of cytokines to cooperate in inducing the responses. Cytokines are also able to amplify the response by inducing the production of other cytokines leading to cascades and networks of interacting cytokines.
It is known that some cytokines are involved in the up and down regulation of immune and inflammatory leukocytes, and in regulation of activity in connective tissue and neural, epithelial, endothelial, and other cell types which are involved in tissue repair and restoration of homeostasis.
In general, normal levels of cytokines are benign in their effects on tissues and cells. However, the overproduction of cytokines can have harmful effects on tissues and can result in cellular damage, capillary leakage and even death. In addition, cytokines have been implicated in neointimal hyperplasia or cell proliferation following surgical procedures, cancer, allergy, infection, angiogenesis, and restenosis. At present, it is thought that TNF and interleukin-1 (IL-1) are particularly involved in producing some of these harmful effects. However, it is anticipated that other cytokines present in excessive amounts will result in cellular and tissue damage.
At present, cytokine-mediated cellular damage is generally treated through the administration of drugs such as vaccines, antiviral compounds, antibiotics, antibodies, receptor-site blockers, antisense nucleotides, and anti-adhesion compounds. These drugs have all been designed to target or act on (i.e. block) specific receptor sites on cells.
However, it is important to note that since the cytokines play an important role in normal defense against infection, it is necessary to maintain the ability of the cells to produce adequate amounts of cytokines to prevent infection.
It has been shown by experimental data, set forth in Libby et al. Cascade Model for Restenosis, Circulation, Supplement III, 86:III-47 to III-52 (1992) that a cytokine/growth factor mechanism is involved in the initiation and proliferation of restenosis. It was found that vessel injury induces cytokine expression and causes a continuing growth factor and cytokine cascade which can account for the defective smooth muscle function observed in restenosis. Therefore, it is suggested that control of the cytokine and growth factor levels could prevent damage caused by restenosis.
Furthermore, experimental data has shown that burn and wound injuries can result in damaging levels of cytokines and growth factors and therefore can result in tissue and cell damage. As discussed by J. S. Solomrkin, M. D. in Neutrophil Disorders in Burn Injury: Complement, Cytokines and Organ Injury, J. of Trauma, Vol. 30, No. 12, Supplement, S80-S85, burn injury can induce a cascade of cytokines and growth factors which can cause an inflammatory response which can result in tissue and cellular injury and loss. It is also known that this response occurs with other wound and surgical injuries. In addition, it has been suggested that calpain is involved in the inflammatory response. Therefore, a reduction in the production of these factors will reduce the amount of tissue and cellular damage induced by burn, wound and surgical injury.
The drugs developed to date block the production of cytokines and may interfere with the host defense mechanisms, thereby subjecting individuals to an increased risk of infection. In addition, the drugs currently in use do not reduce the broad-spectrum of tissue damage caused by cytokines and other chemotactic factors.